PROJECT SUMMARY Lung cancer is the leading cause of cancer death in the US and worldwide. Non-small cell lung cancer (NSCLC) accounts for as much as 85% of all lung cancer cases. The five year survival rate (16%) of NSCLC patients is among the lowest in all malignancies and has not been significantly improved over the past three decades. Histone lysine (K) methylation is considered a hallmark of transcriptional and epigenetic regulation of gene expression. This modification is dynamically controlled by histone methylation modifiers, i.e., histone lysine methyltransferases (methylation writers) and demethylases (methylation erasers). In contrast to great advances in our understanding of kinase signaling pathways, the pathogenic roles of histone methylation modifiers in NSCLC are largely unknown. In our search to identify histone methylation modifiers with oncogenic function for NSCLC, we recently found that in NSCLC tumors, the histone H3 lysine 36 (H3K36) demethylase KDM2A (also known as FBXL11 and JHDM1A) is frequently overexpressed. Our results showed that KDM2A knockdown strongly inhibited tumorigenic and metastatic abilities of KDM2A-high NSCLC cells in mouse xenograft models and that overexpression of KDM2A promoted the proliferation and invasion of KDM2A-low NSCLC cells. The long-term goal is to define the role of the histone modifier KDM2A in lung tumorigenicity. Our additional results revealed that KDM2A repressed tumor-suppressive genes, such as the dual-specificity phosphatase 3 (DUSP3). They also indicate that KDM2A enhances ERK1/2 signaling important for cell proliferation and invasion by epigenetically down-regulating the ERK1/2 phosphatase DUSP3. High KDM2A levels were correlated with poor prognosis in two distinct NSCLC patient cohorts, indicating that KDM2A is a novel poor prognostic epigenetic marker. Based on these definitive findings, our central hypothesis is that KDM2A promotes NSCLC by epigenetically repressing tumor suppressor genes via cooperation with KDM2A-associated protein (s). In the proposed study, we seek to understand the role of KDM2A in lung tumorigenicity using molecular mechanistic studies, genome-wide chromatin sequencing approaches, and our new genetic mouse models. Genetically engineered mouse models proposed here would provide in vivo insights into how KDM2A promotes NSCLC. In addition, our studies promise to uncover new cancer-epigenetic mechanisms by which KDM2A promotes lung cancer and will offer a rationale for the development of a KDM2A-targeted therapy as a new epigenetic therapeutic approach for the treatment of a substantial subset of NSCLC patients.